U.S. patent number 4,127,669 [Application Number 05/841,781] was granted by the patent office on 1978-11-28 for [(4-oxo-4h-1-benzopyran-3-yl)oxy] acetic acids and derivatives.
This patent grant is currently assigned to Warner-Lambert Company. Invention is credited to David T. Connor, Maximillian VON Strandtmann, Patricia A. Young.
United States Patent |
4,127,669 |
Connor , et al. |
November 28, 1978 |
[(4-Oxo-4H-1-benzopyran-3-yl)oxy] acetic acids and derivatives
Abstract
Compounds of formula I: ##STR1## wherein Y is hydrogen, lower
alkyl, halogen or lower alkoxy; X is carboxy, alkoxycarbonyl,
carboxamide, cyano or tetrazolo, and their non-toxic,
pharmaceutically acceptable salts are disclosed. These compounds
are useful in the prevention of allergic and asthmatic
reactions.
Inventors: |
Connor; David T. (Ann Arbor,
MI), Young; Patricia A. (Madison, NJ), VON Strandtmann;
Maximillian (New Castle, DE) |
Assignee: |
Warner-Lambert Company (Morris
Plains, NJ)
|
Family
ID: |
25285676 |
Appl.
No.: |
05/841,781 |
Filed: |
October 13, 1977 |
Current U.S.
Class: |
514/456; 548/252;
549/400 |
Current CPC
Class: |
C07D
311/22 (20130101); C07D 405/12 (20130101) |
Current International
Class: |
C07D
405/00 (20060101); C07D 405/12 (20060101); C07D
311/00 (20060101); C07D 311/22 (20060101); A61K
031/35 (); C07D 311/76 (); C07D 257/04 (); A61K
031/41 () |
Field of
Search: |
;260/345.2,345.5
;424/283 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3849446 |
November 1974 |
Strandtmann et al. |
|
Primary Examiner: Chan; Nicky
Attorney, Agent or Firm: Graddis; Albert H. Chow; Frank S.
Kelly; Anne M.
Claims
We claim:
1. A compound of the formula I: ##STR14## wherein Y is hydrogen,
lower alkyl, halogen or lower alkoxy; X is carboxy, alkoxycarbonyl,
carboxamide or cyano, and the non-toxic, pharmaceutically
acceptable salts thereof.
2. The compound according to claim 1 wherein Y is hydrogen or lower
alkoxy.
3. The compound according to claim 1 which is methyl
[(8-methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetate.
4. The compound according to claim 1 which is methyl
[(4-oxo-4H-1-benzopyran-3-yl)oxy]acetate.
5. The compound according to claim 1 which is
[(8-methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetic acid.
6. The compound according to claim 1 which is
[(4-oxo-4H-1-benzopyran-3-yl)oxy]acetic acid.
7. The compound according to claim 1 which is
2-[(4-oxo-4H-1-benzopyran-3-yl)oxy]acetamide.
8. The compound according to claim 1 which is
[(4-oxo-4H-1-benzopyran-3-yl)oxy]acetonitrile.
9. A pharmaceutical composition for inhibiting reagin-mediated
allergic manifestations in mammals in need thereof, which comprises
an effective amount of a compound of the formula I: ##STR15##
wherein Y is hydrogen, lower alkyl, halogen or lower alkoxy; X is
carboxy, alkoxycarbonyl, carboxamide or cyano, and the non-toxic,
pharmaceutically acceptable salts thereof together with a
pharmaceutically acceptable carrier therefor.
10. A method for inhibiting reagin-mediated allergic manifestations
in mammals in need thereof, which comprises the administration of
an effective amount of a compound of the formula I: ##STR16##
wherein Y is hydrogen, lower alkyl, halogen or lower alkoxy; X is
carboxy, alkoxycarbonyl, carboxamide or cyano, and the non-toxic,
pharmaceutically acceptable salts thereof.
Description
This invention relates to compounds of formula I: ##STR2## wherein
Y is hydrogen, lower alkyl, halogen or lower alkoxy; X is carboxy,
alkoxycarbonyl, carboxamide, cyano or tetrazolo.
Also embraced within the scope of this invention are the non-toxic,
pharmaceutically acceptable salts of the compounds of formula I
such as the sodium salt, the calcium salt and the like. Especially
preferred are those compounds of the formula I wherein Y is
hydrogen or lower alkoxy.
The compounds of the formula I are prepared by the route shown in
reaction Scheme A from 3-hydroxychromones: ##STR3##
The starting 3-hydroxychromones were prepared by the method of F.
Arndt and B. Eistert, Chem. Berichte, 62:36 (1929) wherein
chromanone (unsubstituted or substituted by lower alkyl, halogen or
lower alkoxy on the aromatic ring) is reacted with amyl nitrite to
obtain the correspondingly substituted 3-nitroso chromanone which
may then be hydrolyzed to obtain the desired 3-hydroxychromone
starting material.
The starting 3-hydroxychromones may also be prepared according to
the reaction Scheme B from 3-(methylsulfinyl) chromanones:
##STR4##
In aforementioned Scheme B, the 3-(methylsulfinyl)-chromanones are
prepared according to a general process described by M. von
Strandtmann, et al., in J. Heterocyclic Chem. 9:171 (1972) whereby
a salicyclic ester (which may be unsubstituted or substituted by
lower alkyl, halogen, lower alkoxy) is treated with sodium
methylsulfinyl carbanion generated by the action of sodium hydride
on dimethylsulfoxide to obtain a correspondingly substituted
ortho-hydroxy-.omega.-(methylsulfinyl)acetophenone which is then
cyclized by reaction with 1 mole of formaldehyde to obtain the
desired 3-(methylsulfinyl)chromanone.
The compounds of this invention having the formula I are active in
the prevention of allergic conditions (typically, asthmatic
reactions) in mammals such as rats as evidenced by positive results
in the passive cutaneous anaphylaxis screen (PCA Test). The PCA
screen is a modification of the procedure described by I. Mota,
Life Sciences, Vol. 4, No. 7:465-474 (1963) and Z. Ovary and O.
Bier, Proc. Soc. Exptl. Biol. Med., 81:584-586 (1952) and provides
a measure of the effectiveness of test compounds in inhibiting the
release or action of toxic products arising from the combination of
reaginic antibodies with specific antigens. These toxic products
are causative factors in such disorders as bronchial allergic
asthma (extrinsic reagins), exercise asthma, cold asthma, hay
fever, perennial allergic rhinitis, food allergies, serum or drug
allergies, insect sting allergies, angioneurotic edema, atopic
dermatitis, including infantile excema, urticaria, dermographism,
dermatoconjunctivitis, acute allergic conjunctivitis, chronic
allergic conjunctivitis, and the like.
Inhibition of reaginic antigen/antibody reactions in experimental
animals such as rats is regarded as representative of inhibition of
human reaginic antigen/antibody reactions which occur during
allergic episodes.
Thus, the compounds of this invention having the formula I are
active for the inhibition of reagin-mediated allergic disorders in
mammals in need thereof at dose levels of from about about 0.5 to
about 100 mg/kg of body weight when administered parenterally or by
pulmonary administration via the buccal cavity. Thus, for example,
[(8-methoxy-4-oxo-4H-benzopyran-3-yl)-oxy]acetic acid (the compound
of Example 3) shows a 20% inhibition of the allergic response at
0.5 mg/kg when administered intervenously to rats in the passive
cutaneous anaphalaxis (PCA) screen. Accordingly, the compounds of
this invention having the formula I are useful in the treatment of
asthma, hay fever and other allergic conditions.
In use, the compounds of the invention having the formula I may be
combined with parenterally acceptable vehicles, such as gum
tragacanth, in saline suspension, to provide dosage forms suitable
for parenteral administration.
For pulmonary administration, the compounds of the invention having
the formula I in dry powder form may be formulated with non-toxic,
pharmaceutically acceptable propellants known to the pharmacist's
art or they may be dispensed in powder form from a powder
inhalation device. Compositions in the form of dry powders
preferably may include a solid fine powder diluent.
In all of the above formulas, and throughout the specification, the
terms "lower alkyl" and "lower alkoxy" are meant to include lower
aliphatic hydrocarbons having 1 to 7 carbon atoms (preferably 1 to
4 carbon atoms) in the carbon chain, such as methyl, ethyl, propyl,
isopropyl, butyl or isobutyl; and the term "halogen" is meant to
include bromine, chlorine, iodine and fluorine.
To further illustrate the practice of this invention, the following
examples are included.
EXAMPLE 1 ##STR5##
Methyl[(8-methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetate
A mixture of 3-hydroxy-8-methoxychromone (1.92 g, 0.01 mole),
methyl chloracetate (1.08 g, 0.01 mole) and potassium carbonate
(1.0 g, 0.01 mole) in dimethylformamide (20 ml) is stirred at
100.degree. C. under nitrogen for 4 hrs. The reaction mixture is
allowed to stand at room temperature overnight, poured into water,
filtered, washed with water and sucked dry. Recrystallization from
ethanol gives white crystals (2.3 g, 88%), mp
137.degree.-138.degree. C.
Anal. Calcd, for C.sub.13 H.sub.12 O.sub.6 : C, 59.09; H, 4.58.
Found: C, 59.04; H, 4.67.
EXAMPLE 2 ##STR6##
Methyl [(4-oxo-4H-1-benzopyran-3-yl)oxy]acetate
Prepared from 3-hydroxychromone (12 g, 0.074 mole) by the general
method described in Example 1. Recrystallization from absolute
ethanol gives light brown crystals (13.2 g, 83%), mp
114.degree.-116.degree. C.
Anal. Calcd. for C.sub.12 H.sub.10 O.sub.5 : C, 61.54; H, 4.30.
Found: C, 61.57; H, 4.40.
EXAMPLE 3 ##STR7##
[(8-Methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetic acid
A suspension of methyl
[(8-methoxy-4-oxo-4H-1-benzopyran-3-yl)oxy]acetate (200 mg) in 6N
hydrochloric acid (20 ml) is stirred at 100.degree. C. for 3 hrs.
under nitrogen. The reaction is cooled and the product filtered off
and sucked dry. Recrystallization from methanol gives white
crystals (180 mg. 86%), mp 215.degree.-217.degree. C.
Anal. Calcd. for C.sub.12 H.sub.10 O.sub.6 : C, 57.60; H, 4.03.
Found: C, 57.47; H, 4.24.
EXAMPLE 4 ##STR8##
[(4-Oxo-4H-1-benzopyran-3-yl)oxy]acetic acid
Prepared from methyl [(4-oxo-4H-1-benzopyran-3-yl)oxy]acetate (7.3
g) by the general method described in Example 3. Recrystallization
from absolute ethanol gives tan colored crystals (3.7 g, 54%), mp
154.degree.-164.degree. C.
Anal. Calcd. for C.sub.11 H.sub.8 O.sub.5 : C, 60.00; H, 3.66.
Found: C, 59.84; H, 3.83.
EXAMPLE 5 ##STR9##
2-[(4-Oxo-4H-1-benzopyran-3-yl)oxy]acetamide
Ammonia is bubbled through a cooled (ice-bath) suspension of methyl
[(4-oxo-4H-1-benzopyran-3-yl)oxy]acetate (2 g) in ethanol (100 ml)
for 15 min. An homogeneous solution formed and is stirred at room
temperature for 3 hrs. The solvents are removed at reduced pressure
to give a brown gum, which crystallizes from methanol.
Recrystallization from dimethylformamide gives white crystals (450
mg, 24%), mp 208.degree.-210.degree. C.
Anal. Calcd. for C.sub.11 H.sub.9 NO.sub.4 : C, 60.27; H, 4.14; N,
6.39. Found: C, 60.09; H, 4.18; N, 6.49.
EXAMPLE 6 ##STR10##
[(4-Oxo-4H-1-benzopyran-3-yl)oxy]acetonitrile
A mixture of 3-hydroxychromone (4.86 g, 0.03 mole),
chloroacetonitrile (2.26 g, 0.03 mole) and potassium carbonate (3.0
g, 0.02 mole) in dimethylformamide (40 ml) is stirred at
100.degree. C. under nitrogen for 4 hrs. The reaction mixture is
cooled, poured into water (200 ml), filtered, washed with water and
sucked dry. Recrystallization from methanol gives white crystals
(4.7 g, 94%), mp 145.degree.-146.degree. C.
Anal. Calcd. for C.sub.11 H.sub.7 NO.sub.3 : C, 65.57; H, 3.51; N,
6.96. Found: C, 65.56; H, 3.54; N, 6.85.
EXAMPLE 7 ##STR11##
3-(1H-Tetrazol-5-ylmethoxy)-4H-1-benzopyran-4-one
A mixture of [(4-oxo-4H-1-benzopyran-3-yl)oxy]acetonitrile (2.0 g,
0.01 mole), sodium azide (0.715 g, 0.011 mole) and ammonium
chloride (0.56 g, 0.012 mole) in DMF (10 ml) is heated at
125.degree. C. for 7 hrs. under nitrogen. The reaction is cooled
overnight and then poured into excess cold water. The aqueous is
acidified with 5N hydrochloric acid and the insoluble product is
filtered, washed with fresh water and sucked dry. Recrystallization
from absolute ethanol gives beige colored crystals (1.45 g, 60%),
mp 194.degree.-196.degree. C.
Anal. Calcd. for C.sub.11 H.sub.8 N.sub.4 O.sub.3 : C, 54.10; H,
3.30; N, 22.94. Found: C, 53.83; H, 3.34; N, 22.76.
EXAMPLE 8 ##STR12##
3-Hydroxychromone (1) and 3-(methylthio)chromone (2)
A mixture of 3-(methylsulfinyl)chromanone (11 g), methanol (100 ml)
and 1N hydrochloric acid (100 ml) is stirred at room temperature
for 20 hrs. The methanol is removed at reduced pressure, and the
aqueous residue is extracted with chloroform. The chloroform
extracts are combined, extracted with 1N sodium hydroxide solution,
washed with water, dried over MgSO.sub.4 and evaporated to give an
oil. The oil is heated at 100.degree. C. in 5N hydrochloric acid
(100 ml) for 5 hrs. The solution is cooled, and the product which
precipitated is filtered off. Recrystallization from methanol gives
3-(methylthio)chromone (2) as white crystals (7.2 g, 72%), mp
103.degree.-105.degree. C.
Anal. Calcd. for C.sub.10 H.sub.8 O.sub.2 S: C, 62.48; H, 4.20; S,
16.68. Found: C, 62.34; H, 4.26; S, 16.24.
The sodium hydroxide solution extracts are acidified with 5N
hydrochloric acid and extracted with chloroform. The chloroform
extracts are dried over MgSO.sub.4 and evaporated to a solid
product. Recrystallization from ethanol gives 3-hydroxychromone (1)
as white crystals (2.1 g, 25%) mp 178.degree.-179.degree. C.
Anal. Calcd. for C.sub.9 H.sub.6 O.sub.3 : C, 66.67; H, 3.73. Found
C, 66.27; H, 3.79.
EXAMPLE 9 ##STR13##
8-Methoxy-3-hydroxychromone (1) and
8-methoxy-3-(methylthio)chromone (2)
A mixture of 8-methoxy-3-(methylsulfinyl)chromanone (20 g),
methanol (100 ml) and 1N hydrochloric acid (100 ml) is stirred at
room temperature for 20 hrs. The methanol is removed at reduced
pressure and the aqueous residue is extracted with chloroform. The
chloroform extracts are combined, extracted with 1N sodium
hydroxide solution, washed with water, dried over MgSO.sub.4 and
evaporated to give an oil. The oil is heated at 100.degree. C. in
5N hydrochloric acid (100 ml) for 5 hrs. The solution is cooled and
the product which precipitated is filtered off. Recrystallization
from ethanol gives 8-methoxy-3-(methylthio)chromone (2) as white
crystals (12.1 g, 65%), mp 113.degree.-115.degree. C.
Anal. Calcd. for C.sub.11 H.sub.10 O.sub.3 S: C, 59.44; H, 4.54; S,
14.43. Found: C, 59.23; H, 4.58; S, 14.48.
The sodium hydroxide solution extracts are acidified with 5N
hydrochloric acid and extracted with chloroform. The chloroform
extracts are dried over MgSO.sub.4 and evaporated to give a yellow
solid. Recrystallization from ethanol gives
8-methoxy-3-hydroxychromone (1) as yellow crystals (3.64 g, 23%),
mp 180.degree.-183.degree. C.
Anal. Calcd. for C.sub.10 H.sub.8 O.sub.3 : C, 62.50; H, 4.20.
Found: C, 62.77; H, 4.19.
* * * * *